Pneumonectomy (PNX) in adult canines mimics the consequences of restrictive lung disease and is a robust model of compensatory lung growth (CLG), characterized by early alveolar cellular proliferation-hypertrophy, progressive septal remodeling, gradual normalization of acinar architecture and incremental restoration of lung function over many months. Post-PNX mechanical signals activate nearly all the major homeostatic pathways; downstream responses are very sensitive to pharmacological stimulation but exogenously enhanced alveolar tissue growth has not been mirrored by functional enhancement. This structure-function gap represents a key obstacle to translational progress in the field. Potential reasons for the gap include: a) uneven and/or over- stimulation of septal components, b) lack of proportionally enhanced septal remodeling to optimize the gas exchange, barrier and minimize architecture distortion, and c) need for lung-specific titratable delivery of growth promoters. Our goal is to develop a strategy of balanced enhancement of alveolar growth/remodeling aimed at minimizing distortion and increasing the likelihood of functional benefit. Our hypothesis is that sustained low-dose inhalational nanoparticle (NP) delivery of complementary growth-promoting agents selected for balanced stimulation of alveolar growth/remodeling enhances post-PNX lung structure and function. Biocompatible biodegradable poly(lactic-co-glycolic acid) or PLGA-encapsulated NPs will be synthesized each containing a known growth promoter: all-trans retinoic acid (RA), peptide or cDNA of keratinocyte growth factor (KGF) and its receptor (KGFR), or erythropoietin (EPO) and its receptor (EPOR), to be administered in combination to proportionally stimulate the alveolar epithelium, interstitium and endothelium, promote/protect beneficial septal remodeling, and preserve/restore normal architecture. Magnetic tag and fluorescent labels may be incorporated into NPs as tracers initially, but omitted in final therapeutic formulations. Aim 1: Characterize i vitro dose-response, duration of action, and biosafety of NPs containing individual and combination growth promoting agent in human lung cells. Optimize NP formulations for sustained release and modest action. Aim 2: Determine in vivo biological action of NPs containing combinations of growth promoting agents. NPs in suspension will be nebulized into adult rats and pilot dogs to characterize bio-distribution and biosafety of chronic administration. Aim 3: Determine the long-term effects of NP cocktails on post-PNX CLG and function in adult canines. Therapeutic response will be monitored using non-invasive imaging (HRCT and UTE MRI), physiological testing (rest and exercise), and detailed structural analysis. This novel multi pathway paradigm for lung regeneration parallels the approach used in cancer chemotherapy, combines state-of-the-art nanotechnology, imaging and physiological techniques, and forges inter-disciplinary collaborations. Results will impact fundamental concepts of lung regeneration-repair, bridge a key knowledge gap in the manipulation of lung growth, and are immediately translatable to the bedside.